CN102762559A - Diphenyl-pyrazolopyrdine derivatives, preparation thereof, and use thereof as nuclear receptor not modulators - Google Patents
Diphenyl-pyrazolopyrdine derivatives, preparation thereof, and use thereof as nuclear receptor not modulators Download PDFInfo
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- CN102762559A CN102762559A CN2010800626000A CN201080062600A CN102762559A CN 102762559 A CN102762559 A CN 102762559A CN 2010800626000 A CN2010800626000 A CN 2010800626000A CN 201080062600 A CN201080062600 A CN 201080062600A CN 102762559 A CN102762559 A CN 102762559A
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- Prior art keywords
- pyridine
- pyrazolo
- methyl
- representes
- compound
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- AERHMYAISMZODY-UHFFFAOYSA-N 4-chloro-3-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=C(Cl)C(C2=CC3=CC(=NN3C=C2)C=2C=CC(F)=CC=2)=C1 AERHMYAISMZODY-UHFFFAOYSA-N 0.000 description 1
- AUTBPCSTSHLHRU-UHFFFAOYSA-N 5-bromo-2-(4-chlorophenyl)pyrazolo[1,5-a]pyridine Chemical compound C1=CC(Cl)=CC=C1C1=NN2C=CC(Br)=CC2=C1 AUTBPCSTSHLHRU-UHFFFAOYSA-N 0.000 description 1
- ZWLVHMWWCZSLJJ-UHFFFAOYSA-N 5-bromo-2-(4-methylphenyl)pyrazolo[1,5-a]pyridine Chemical compound C1=CC(C)=CC=C1C1=NN2C=CC(Br)=CC2=C1 ZWLVHMWWCZSLJJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VFRIQWYFKHVDNK-UHFFFAOYSA-N CC1(C)OB(c2cc3cc(-c(cc4)ccc4F)n[n]3cc2)OC1(C)C Chemical compound CC1(C)OB(c2cc3cc(-c(cc4)ccc4F)n[n]3cc2)OC1(C)C VFRIQWYFKHVDNK-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
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- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
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- 108060001084 Luciferase Proteins 0.000 description 1
- 108010093175 Member 2 Group A Nuclear Receptor Subfamily 4 Proteins 0.000 description 1
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- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- 229960001171 acetohydroxamic acid Drugs 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000002313 adhesive film Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- UMPRJGKLMUDRHL-UHFFFAOYSA-N ethyl 4-fluorobenzoate Chemical compound CCOC(=O)C1=CC=C(F)C=C1 UMPRJGKLMUDRHL-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
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- KORDHIFXVOEGAA-UHFFFAOYSA-N methyl 3-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzoate Chemical compound COC(=O)C1=CC=CC(C2=CC3=CC(=NN3C=C2)C=2C=CC(F)=CC=2)=C1 KORDHIFXVOEGAA-UHFFFAOYSA-N 0.000 description 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
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- 210000000214 mouth Anatomy 0.000 description 1
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- 150000002825 nitriles Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
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- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
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- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
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- 239000002904 solvent Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
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- 150000003512 tertiary amines Chemical class 0.000 description 1
- LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical compound C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to formula (I), in which R is a hydrogen or halogen atom or a (C1-C6) alkyl group; X is one or more substituents selected from a hydrogen or halogen atom, a (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, cyano, hydroxy, or hydroxy(C1-C6)alkyl group; Y is a hydrogen or halogen atom or a (C1-C6)alkyl group; R1 is an NR2R3 or OR4 group; R2 and R3 independently are a hydrogen atom, a (C1-C6)alkyl, hydroxy(C1-C6)alkyl or oxo(C1-C6)alkyl group, or R2 and R3, together with the nitrogen atom supporting the same, form a heterocycle optionally substituted by a (C1-C6)alkyl, hydroxy, or oxo group; and R4 is a (C1-C6)alkyl, hydroxy(C1-C6)alkyl, or oxo(C1-C6)alkyl group, in the base or acid addition salt state. Said formula can be used therapeutically for treating or preventing diseases linked to the nuclear receptors Nurr-1, also known as NR4A2, NOT, TINUR, RNR-1, and HZF3.
Description
The present invention relates to diphenylpypazole and pyridine derivate, their preparation and their therepic use in the disease of treating or prevent to relate to Nurr-1 nuclear receptor (also being known as NR4A2, NOT, TINUR, RNR-1 and HZF3).
One of the present invention themes as formula (I) compound:
Wherein:
R representes hydrogen or halogen atom or (C1-C6) alkyl;
X representes one or more following substituting groups that are selected from: hydrogen or halogen atom, (C1-C6) alkyl, halo (C1-C6) alkyl, (C1-C6) alkoxyl group, halo (C1-C6) alkoxyl group, cyanic acid, hydroxyl or hydroxyl (C1-C6) alkyl;
Y representes hydrogen or halogen atom or (C1-C6) alkyl;
R1 representes NR2R3 or OR4;
R2 and R3 represent Wasserstoffatoms or (C1-C6) alkyl, hydroxyl (C1-C6) alkyl or oxo (C1-C6) alkyl independently of one another, perhaps R2 and R3 and the nitrogen-atoms that carries them form optional by (C1-C6) alkyl, hydroxyl or the substituted heterocycle of oxo group,
R4 representes (C1-C6) alkyl, hydroxyl (C1-C6) alkyl or oxo (C1-C6) alkyl,
With the form of alkali or the form of acid salt.
Formula (I) compound can comprise one or more unsymmetrical carbons.Therefore they can enantiomer or the form of diastereomer exist.These enantiomers and diastereomer and their mixture (comprising racemic mixture) have constituted a part of the present invention.
Formula (I) compound can exist with the form of alkali or the form of acid salt.This type of additive salt has constituted a part of the present invention.
These salt can use pharmaceutically acceptable acid preparation, but the salt of other useful acid (for example, being used for the acid of purifying or separate type (I) compound) has also constituted a part of the present invention.
The form of all right hydrate of formula (I) compound or solvate exists, promptly to associate or the bonded form with one or more water moleculess or with solvent.This type of hydrate and solvate also constitute a part of the present invention.
In context of the present invention, use following definition:
-group (C
x-C
t): the group that comprises x to t carbon atom;
-halogen atom: fluorine, chlorine, bromine or iodine;
-alkyl: straight chain, side chain or cyclic saturated aliphatic groups, optional by straight chain, side chain or the replacement of cyclic saturated alkyl.The instance that can mention comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl cyclopropyl, cyclopropyl methyl etc.;
-alkoxyl group :-O-alkyl, wherein alkyl is like preceding definition;
-haloalkyl: by the substituted alkyl of one or more identical or different halogen atoms.The instance that can mention comprises CF
3, CH
2CF
3, CHF
2And CCl
3
-hydroxyalkyl: by the substituted alkyl of hydroxyl.The instance that can mention comprises CH
2OH, CH
2CH
2OH etc.;
-oxoalkyl group: by the substituted alkyl of oxo group (C=O).The instance that can mention comprises CH
3CO, CH
3COCH
2Deng;
-halogenated alkoxy: by one or more identical or different halogen atoms substituted-the O-alkyl, wherein alkyl is like preceding definition.The instance that can mention comprises OCF
3, OCHF
2And OCCl
3
-aryl: the monocycle or the Bicyclic group that contain 6-10 atom.The instance of the aryl that can mention comprises phenyl and naphthyl;
-heterocyclic radical: the cyclic group of saturated nitrogenous optional bridging comprises 5-9 carbon atom, at least one nitrogen-atoms and randomly comprises 1-3 other heteroatomss, like oxygen, nitrogen or sulphur.What especially can mention is piperidyl, piperazinyl, pyrrolidyl, morpholinyl etc.
In formula (I) compound of theme of the present invention, first group of compound is following compounds:
R representes hydrogen or chlorine atom,
X representes one or more following substituting groups that are selected from: halogen atom, (C1-C6) alkyl, halo (C1-C6) alkyl, (C1-C6) alkoxyl group, halo (C1-C6) alkoxyl group or cyanic acid,
Y representes Wasserstoffatoms, halogen atom or (C1-C6) alkyl;
R1 representes OR4,
R4 representes methyl,
Be the form of alkali or the form of acid salt.
In formula (I) compound of theme of the present invention, second group of compound is following compounds:
R representes hydrogen or chlorine atom,
X representes one or more following substituting groups that are selected from: chlorine or fluorine atom, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy or cyanic acid,
Y representes hydrogen, chlorine or fluorine atom or methyl,
R1 representes OR4,
R4 representes methyl,
With the form of alkali or the form of acid salt.
In formula (I) compound of theme of the present invention, the 3rd group of compound is following compounds:
R representes hydrogen or chlorine atom,
X representes one or more following substituting groups that are selected from: halogen atom, (C1-C6) alkyl, halo (C1-C6) alkyl, (C1-C6) alkoxyl group, halo (C1-C6) alkoxyl group or cyanic acid,
Y representes Wasserstoffatoms, halogen atom or (C1-C6) alkyl;
R1 representes NR2R3,
R2 and R3 represent Wasserstoffatoms or methyl, ethyl, sec.-propyl or cyclopropyl independently of one another, perhaps R2 and R3 and the nitrogen-atoms that carries them form optional by substituted morpholinyl of hydroxyl or pyrrolidyl,
With the form of alkali or the form of acid salt.
In formula (I) compound of theme of the present invention, the 4th group of compound is following compounds:
R representes hydrogen or chlorine atom,
X representes one or more following substituting groups that are selected from: chlorine or fluorine atom, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy or cyanic acid,
Y representes hydrogen or chlorine atom or methyl,
R1 representes NR2R3,
R2 and R3 represent Wasserstoffatoms or methyl, ethyl, sec.-propyl or cyclopropyl independently of one another, perhaps R2 and R3 and the nitrogen-atoms that carries them form optional by substituted morpholinyl of hydroxyl or pyrrolidyl,
With the form of alkali or the form of acid salt.
As above defined one to four group combination has also constituted a part of the present invention.
In formula (I) compound of theme of the present invention, the compound that can especially mention is a following compounds:
3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl] benzoic acid methyl ester
3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl] BM
3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl]-N, the N-dimethyl benzamide
3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] oil of Niobe
3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-isopropyl benzene methane amide
3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N, the N-dimethyl benzamide
{ 3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] phenyl } morpholine-4-base-ketone
3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-2, the N-dimethyl benzamide
2-chloro-5-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
4-chloro-3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-4, the N-dimethyl benzamide
2-fluoro-4-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
N-cyclopropyl-3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] BM
{ 3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] phenyl } tetramethyleneimine-1-base ketone
3-[2-(2, the 6-difluorophenyl) pyrazolos [1,5-a] pyridine-5-base-methyl benzamide
3-[2-(2-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
N-methyl-3-[2-(4-trifluoromethyl) pyrazolo [1,5-a] pyridine-5-yl] BM
4-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
2-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
{ 3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] phenyl }-(3-hydroxyl pyrrolidine-1-yl) ketone
3-[2-(2,4 difluorobenzene base) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
N-methyl-3-[2-(4-Trifluoromethoxyphen-l) pyrazolo [1,5-a] pyridine-5-yl] BM
3-[2-(3, the 4-difluorophenyl) pyrazolos [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(3, the 5-difluorophenyl) pyrazolos [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(3-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
N-methyl-3-(2-p-methylphenyl pyrazolo [1,5-a] pyridine-5-yl) BM
3-[2-(4-p-methoxy-phenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(3, the 4-3,5-dimethylphenyl) pyrazolos [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(4-cyano-phenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(2, the 3-difluorophenyl) pyrazolos [1,5-a] pyridine-5-yl]-N-methyl-benzamide
N-methyl-3-(2-o-tolyl pyrazolo [1,5-a] pyridine-5-yl) BM
3-[3-chloro-2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide is according to the present invention, and general formula (I) compound can be according to the method preparation of reaction equation 1.
Reaction equation 1
According to reaction equation 1, (wherein R1 representes OR4 to general formula (Ia) compound, and R4 representes alkyl ALK; R representes Wasserstoffatoms, and X and Y are like preceding definition) can prepare through the coupled reaction between metal (for example palladium) catalytic general formula (II) compound and general formula (III) verivate, in its formula of (II) compound; R representes Wasserstoffatoms, and X representes halogen atom like preceding definition and Hal, in general formula (III) verivate; Y and ALK are like preceding definition, and Z representes boron derivative.
According to reaction equation 1, general formula (Ib) compound (wherein R1 representes OR4, and R representes Wasserstoffatoms, and X and Y are like preceding definition, and R4 representes Wasserstoffatoms) can utilize alkali such as the hydrolysis reaction of sodium hydroxide in water-based-alcohol property medium to prepare through general formula (Ia) compound.
According to reaction equation 1 route A, (wherein R1 representes NR2R3 to general formula (Ic) compound, and R representes Wasserstoffatoms; X, Y, R2 and R3 are like preceding definition) can prepare through the coupled reaction between metal (for example palladium) catalytic general formula (II) compound and general formula (IV) verivate, in its formula of (II) compound, R representes Wasserstoffatoms; X is like preceding definition, and Hal representes halogen atom, in general formula (IV) verivate; Wherein Y, R2 and R3 are like preceding definition, and Z representes boron derivative.
According to reaction equation 1 route B, (wherein R1 representes NR2R3 to general formula (Ic) compound, and R representes Wasserstoffatoms; X, Y, R2 and R3 are like preceding definition) can be prepared through as follows: (wherein R1 representes OR4 to general formula (Ia) compound; R4 representes alkyl ALK, and R representes Wasserstoffatoms, and X and Y are like preceding definition) in solution, perhaps react (according to D.Glynn in the presence of trimethylaluminium with the amine of logical formula V (wherein R2 and R3 are like preceding definition) with tertiary amine such as DABCO complexing; D.Bernier and S.Woodward in Tetrahedron Letters; 2008,49, the method for describing among the 5687-5688).
According to reaction equation 1 route C; (wherein R1 representes NR2R3 to general formula (Ic) compound; R representes Wasserstoffatoms, and X, Y, R2 and R3 are like preceding definition) can (wherein R1 representes OR4, and R representes Wasserstoffatoms through general formula (Ib) compound; X and Y are like preceding definition, and R4 representes Wasserstoffatoms) and the amine of logical formula V (wherein R2 and R3 are like preceding definition) between in the presence of acid activators such as isobutyl chlorocarbonate, react and prepare.
According to reaction equation 1 route D; (wherein R1 representes NR2R3 to general formula (Ic) compound; R representes Wasserstoffatoms, and X, Y, R2 and R3 are like preceding definition) can (wherein R representes Wasserstoffatoms, and X is like preceding definition through metal (for example palladium) catalytic general formula (VI) compound; Z representes boron derivative) and general formula (VII) verivate (wherein Y, R2 and R3 are like preceding definition, and Hal representes halogen atom) between coupled reaction and prepare.
General formula (Ic) compound (wherein R2 and R3 represent Wasserstoffatoms separately) also can prepare according to the method that reaction equation 2 is described.
Reaction equation 2
In reaction equation 2, general formula (Ic) compound (wherein R1 representes NH2, and R representes Wasserstoffatoms, and X and Y are like preceding definition) can utilize hydrogen peroxide to prepare at the hydrolysis reaction in the presence of the alkali through the nitrile (for example) of general formula (IX).General formula (IX) compound can (wherein R representes Wasserstoffatoms through metal (for example palladium) catalytic general formula (II) compound; X is like preceding definition; Hal representes halogen atom) and general formula (VIII) verivate (Y is like preceding definition, and CN representes cyanic acid, and Z representes boron derivative) between coupled reaction and obtain.
According to the present invention, general formula (I) compound can be according to the method preparation of describing in the reaction equation 3.
Reaction equation 3
According to reaction equation 3, general formula (Id) compound (wherein X, Y and R1 are like preceding definition, and R representes halogen atom Hal) can prepare through compound (Ia) or close electric halogenating reaction (Ic), and for example chlorination reaction is utilized reagent such as N-chlorosuccinimide.
According to the present invention, general formula (II) and (VI) compound can be through the method preparation of describing in the reaction equation 4.
Reaction equation 4
At reaction equation 4 route A, general formula (II) compound (wherein X is like preceding definition, and R representes that Wasserstoffatoms and Hal represent halogen atom) can prepare through the effect of O-(mesitylene alkylsulfonyl) oxyamine (MSH) on general formula (XIII) compound (wherein X and Hal are like preceding definition); For example according to Y.Tamura, J.-H.Kim, Y.Miki; H.Hayashi, M.Ikeda, in J.Het.Chem.; The method of 1975,12,481 descriptions.
In reaction equation 4 route B; General formula (II) compound (wherein X is like preceding definition, and R representes Wasserstoffatoms, and Hal representes halogen atom) also can be prepared as follows: general formula (XIII) compound is converted into general formula (XIV) compound (wherein X and Hal are like preceding definition); Through acid anhydrides such as the effect of trifluoroacetic anhydride in the presence of alkali (like triethylamine); Then general formula (II) compound is carried out cyclization in the presence of catalyzer (for example iron(ic)chloride), for example according to K.S.Gudmundsson in Bioorg.Med.Chem., 2005; The method of describing in 13,5346.
Compound (XIII) can be prepared by the effect of compound (XII) through azanol.Compound (XII) can (wherein X be like preceding definition by the picoline of general formula (X) and the ester of general formula (XI); ALK representes alkyl) in the presence of alkaline and obtain, for example according to K.S.Gudmundsson in Bioorg.Med.Chem., 2005; The method of describing in 13,5346.
At last; Compound (VI) (wherein Z representes boron derivative) can be according to preparing through the catalytic for example two coupled reactions of (tetramethyl ethylene ketone (pinacolato)) two boron on compound (II) of metal (for example palladium) shown in the reaction equation 3; According to E.F.DiMauro and R.Vitullo in J.Org.Chem.; The method of describing in 2006,71 (10), 3959.
In reaction equation 1,2,3 and 4, initial compounds and reagent (when their preparation method does not describe) are purchased and can get or be described in the document, perhaps can be according to method of wherein describing or the known method preparation of those of ordinary skill in the art.
According to it on the other hand, theme of the present invention also is formula (VI-1) compound.This compound is as the midbody of synthesis type (I) compound.
Following embodiment has described the preparation of particular compound according to the invention.These embodiment are not restrictive, only play the object of the invention exemplarily is described.The numbering that provides as embodiment is meant the numbering that provides in this paper following table, and they have exemplarily explained the chemical structure and the physical properties of the numerous compounds of the present invention.
Embodiment 1:3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl] benzoic acid methyl ester (compound 1 in the table)
1.1 2-(4-bromopyridine-2-yl)-1-(4-chloro-phenyl-) ethyl ketone
Under nitrogen gas stream, the 4-bromo-2-picoline of 5g (29.07mmol) and the 4-chloro-benzoic acid ethyl ester of 11.27g (61.04mmol) are placed round-bottomed flask, be dissolved in the 50mL anhydrous tetrahydro furan.This solution is cooled to 5 ° of C, drips the hexamethyl two silica-based Lithamide solution (tetrahydrofuran solution of 1M) of 70mL (70mmol).After the dropping, mixture is cooled to 5 ° of C stirring at room 2 hours, slowly adds 100mL water then.Medium uses 250mL ETHYLE ACETATE and the dilution of 100mL water then.Isolate organic phase, water uses the 100mL ethyl acetate extraction twice.Merge organic phase then, use dried over sodium sulfate, and filter.Then 15g silicon-dioxide is added to filtrating, under reduced pressure concentrate then.The powder that obtains uses the mixture wash-out of hexanaphthene and ETHYLE ACETATE (9/1) as the solid sediment of silica gel column chromatography.Obtain 8.4g (93%) product, be the yellow powder form.
LC-MS：M+H=310
1H NMR (DMSO) δ (ppm): 4.6 (s, 2H); 6.4 (s, 1H); 7.4 (s, 1H); 7.5 to 7.6 (m, 6H); 7.7 (s, 1H); 7.9 (d, 2H); 8.1 (d, 2H); 8.3 (d, 1H); 8.4 (d, 1H); 15.0 (s, 1H) (keto-acid/enol form mixture: 40/60).
1.2 2-(4-bromopyridine-2-yl)-1-(4-chloro-phenyl-) ethyl ketone oxime
2-(4-bromopyridine-2-yl)-1-(4-chloro-phenyl-) ethyl ketone of 8.4g (27.05mmol) is placed round-bottomed flask (containing 150mL ethanol).Add 22mL (272.56mmol) pyridine and 7.5g (107.93mmol) azanol mono-hydrochloric salts.Mixture is then stirring at room 5 hours, and reaction medium under reduced pressure concentrates then, up to obtaining the pasty state yellow solid, it is dissolved in 400mL ETHYLE ACETATE and the 400mL water.Isolate organic phase, water uses the 200mL ethyl acetate extraction three times.Merge organic phase then, use dried over sodium sulfate, and filter.Filtrating under reduced pressure concentrates, and obtains 8.1g (91.9%) product, is the form of blue powder.
LC-MS：M+H=325
1H?NMR(DMSO)δ(ppm)：4.3(s,2H)；7.45(m,2H)；7.50(d,1H)；7.55(s,1H)；7.75(m,2H)；8.35(d,1H)；11.65(s,1H)。
1.3. 5-bromo-2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine
O-(the 2-mesitylene alkylsulfonyl) acetyl-hydroxamic acid ethyl ester of 12.9g (45.21mmol) is placed round-bottomed flask (containing 1 of 30mL, 4-two
alkane).Solution is cooled to 0 ° of C, adds the perchloric acid (70% the aqueous solution) of 13.5mL (156.60mmol).Add 1 of 10mL then; 4-two
alkane, medium was 0 ° of C vigorous stirring 2 hours 30 minutes.Then medium is poured onto in the ice-cooled water of 350mL.Medium was placed 10 minutes at 0 ° of C, and the white solid of formation is then through going up filtered and recycled (not having complete drying, because product possibly explode under dried forms) at sand core funnel (sinter funnel).The pasty state white solid that obtains uses the ice-cooled water washing of 350mL, is dissolved in 1 of the 250mL that is cooled to about 5 ° of C then, in 2-ethylene dichloride and the 150mL salt solution.Reclaim organic phase and pass through the drainage column filtration.Reclaim filtrating, and 2-(4-bromopyridine-2-yl)-1-(4-chloro-phenyl-) the ethyl ketone oxime (compound that step 1.2 obtains) that drops to the 8.1g (24.88mmol) that is cooled to about 0 ° of C is in 1 of 150mL, in the solution in the 2-ethylene dichloride.
After the interpolation, mixture is warmed to room temperature, and stirred 3 hours.In medium, add 250mL methylene dichloride, 200mL water and the 100mLNaOH aqueous solution (1N) then successively.The mixture that stirring obtains is separated through leaving standstill to make respectively then.Isolate organic phase, water uses the 200mL dichloromethane extraction twice.Merge organic phase then; Go up filtration at drainage column (
70mL liquid phase/liquid-phase extraction post), mix with 15g silicon-dioxide then.Filtrating under reduced pressure concentrates then.Obtain brown ceramic powder, it uses the mixture wash-out of hexanaphthene and methylene dichloride (1/1) as the solid sediment of silica gel column chromatography.Obtain 5.8g (75%) product, be the fluffy solid of little yellow.
LC-MS：M+H=307。
1H?NMR(DMSO)δ(ppm)：7.0(d,1H)；7.1(s,1H)；7.6(d,2H)；8.0(s,1H)；8.1(d,2H)；8.7(d,1H)。
1.4 3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl] benzoic acid methyl ester
5-bromo-2-(4-chloro-phenyl-) pyrazolo [1 of the 0.235g (0.76mmol) that step 1.3 is obtained; 5-a] [1,1 '-two (diphenylphosphine) ferrocene] dichloro of 3-methoxycarbonyl phenyl-boron dihydroxide, 0.750g (2.30mmol) cesium carbonate and 0.065g (0.08mmol) of pyridine, 0.165g (0.92mmol) closes palladium (II) and places round-bottomed flask (the THF-water mixture (9/1) that contains 5mL).Then medium was kept 1 hour 30 minutes at 70 ° of C, be cooled to room temperature then, use the dilution of 30mL methylene dichloride and 30mL water.Two-phase medium is gone up at drainage column (
70mL liquid phase/liquid-phase extraction post) and is filtered, and filtrating under reduced pressure concentrates then.The resistates that obtains chromatography on silica gel, the mixture wash-out of use hexanaphthene and ETHYLE ACETATE (8/2).Obtain 0.200g (72%) expectation product, be the form of cream-coloured powder.
Fusing point (° C): 180-182.
LC-MS：M+H=363。
1H NMR (DMSO) δ (ppm): 3.95 (s, 3H); 7.20 (s, 1H); 7.35 (d, 1H); 7.60 (d, 2H); 7.70 (t, 1H); 8.00 to 8.20 (m, 5H); 8.35 (s, 1H); 8.85 (d, 1H).
Embodiment 2:3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl] BM (compound 2 in the table)
2.1 3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl] cyanobenzene
In the presence of the THF-of 20mL water mixture (9/1); 5-bromo-2-(4-chloro-phenyl-) pyrazolo [1 of the 0.850g (2.76mmol) that will obtain according to the scheme of step 1.3; 5-a] pyridine places round-bottomed flask ([1,1 '-two (diphenylphosphine) ferrocene] dichloro that contains 3-cyano-phenyl boric acid, 2.70g (8.29mmol) cesium carbonate and the 0.225g (0.26mmol) of 0.490g (3.33mmol) closes palladium (II)).Then medium was kept 3 hours at 75 ° of C; Then add other 0.245g (1.66mmol) 3-cyano-phenyl boric acid, 1.35g (4.14mmol) cesium carbonate and 0.115g (0.14mmol) [1; 1 '-two (diphenylphosphine) ferrocene] dichloro closes palladium (II), and medium stirred 1 hour 30 minutes at 75 ° of C.Medium uses 100mL ETHYLE ACETATE and the dilution of 100mL water then.Reclaim organic phase then, water uses the 100mL ethyl acetate extraction twice.Merge organic phase then, use dried over sodium sulfate, and filter.Filtrating under reduced pressure concentrates then, and the resistates that obtains is dissolved in THF, behind the interpolation 10g silicon-dioxide, under reduced pressure concentrates.Resistates is chromatography on silica gel, uses the mixture wash-out of hexanaphthene and ETHYLE ACETATE (8/2).Obtain 0.185g (20.2%) expectation product, be the form of white powder.
LC-MS：M+H=330。
1H?NMR(DMSO)δ(ppm)：7.19(s,1H)；7.37(dd,1H)；7.56(m,2H)；7.74(t,1H)；7.90(m,1H)；8.06(m,2H)；8.15-8.24(m,2H)；8.35(m,1H)；8.82(d,1H)。
2.2 3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl] BM
[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl] cyanobenzene of the 0.150g (0.45mmol) that step 2.1 is obtained places round-bottomed flask (containing the 5mL anhydrous dimethyl sulfoxide).Then medium is cooled to about 10 ° of C, adds 0.100mL (1.17mmol) aqueous hydrogen peroxide solution (35% aqueous solution) and 0.035g (0.25mmol) salt of wormwood.Medium is warmed to room temperature gradually, stirs 1 hour.Then medium is cooled to about 5 ° of C, adds hydrogen peroxide and 0.250g (1.78mmol) salt of wormwood of 0.500mL (5.85mmol).Then with medium stirring at room 1 hour 30 minutes, then add 50mL water.Medium filters through sand core funnel, reclaims powder, and it carries out silica gel column chromatography (through solid sediment), uses the mixture wash-out of methylene dichloride and methyl alcohol (9/1).Obtain 0.090g (56.8%) expectation product, be the form of white powder.
Fusing point (° C): 283-285.
LC-MS：M+H=348。
1H?NMR(DMSO)δ(ppm)：7.17(s,1H)；7.36(dd,1H)；7.47(s,1H)；7.56(m,2H)；7.61(t,1H)；7.94(m,1H)；8.00(m,1H)；8.07(m,2H)；8.11(m,1H)；8.15(s,1H)；8.32(m,1H)；8.82(d,1H)。
Embodiment 3:3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl]-N, N-dimethyl benzamide (compound 3 in the table)
Under nitrogen gas stream, 0.900mL (1.80mmol) dimethylamine solution (2M tetrahydrofuran solution) and 8mL toluene are placed round-bottomed flask.Then medium is cooled to 0 ° of C, drips 0.900mL (1.80mmol) trimethylaluminium solution (2M toluene solution) then.After the dropping, medium stirred 25 minutes at about 0 ° of C, then added 3-[2-(4-chloro-phenyl-) pyrazolo [1, the 5-a] pyridine-5-yl] benzoic acid methyl ester of the 0.200g (0.55mmol) of step 2.1 acquisition.Then medium was kept 3 hours at 90 ° of C, then be cooled to about 0 ° of C.Medium is then through dripping 10mL hydrochloric acid soln (1N) hydrolysis.After the dropping, medium is warmed to room temperature, uses the dilution of 60mL methylene dichloride and 60mL water then.It is about 11 to use sodium hydroxide solution (1N) to be adjusted to the pH of water, and the two-phase medium that obtains filters at the sand core funnel that Celite is being housed.Reclaim filtrating, through drainage column (
70mL liquid phase/liquid-phase extraction post).Reclaim filtrating, behind the interpolation 1.2g silicon-dioxide, under reduced pressure concentrate.The resistates that obtains carries out silica gel column chromatography, uses the mixture wash-out of hexanaphthene and ETHYLE ACETATE (3/7).Obtain 0.121g (58.4%) expectation product, be the form of white powder.
Fusing point (° C): 175-177.
LC-MS：M+H=376。
1H?NMR(DMSO)δ(ppm)：3.02(d,6H)；7.15(s,1H)；7.35(dd,1H)；7.46(m,1H)；7.50-7.67(m,3H)；7.85(m,1H)；7.91(m,1H)；8.00-8.15(m,3H)；8.80(d,1H)。
Embodiment 4:3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide (compound 4 in the table)
This step is carried out according to the method for describing among the embodiment 3; Originate in 3-[2-(4-chloro-phenyl-) pyrazolo [1 of the 0.200g (0.55mmol) of step 3.1 acquisition; 5-a] pyridine-5-yl] benzoic acid methyl ester, 0.900mL (1.80mmol) methylamine solution (2M tetrahydrofuran solution) and 0.900mL (1.80mmol) trimethylaluminium solution (2M toluene solution), in 8mL toluene.Behind the silica gel column chromatography, use the mixture wash-out of hexanaphthene and ETHYLE ACETATE (1/1), obtain 0.151g (75.6%) expectation product, be the form of white powder.
Fusing point (° C): 234-236.
LC-MS：M+H=362。
1H?NMR(DMSO)δ(ppm)：2.85(d,3H)；7.18(s,1H)；7.35(m,1H)；7.51-7.68(m,3H)；7.90(m,1H)；8.00(m,1H)；8.02-8.12(m,3H)；8.28(m,1H)；8.62(m,1H)；8.82(d,1H)。
Embodiment 5:3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] benzoic acid methyl ester (compound 5 in the table)
5.1 2-(4-bromopyridine-2-yl)-1-(4-fluorophenyl) ethyl ketone
Under nitrogen gas stream, the 4-bromo-2-picoline of 5.0g (29.07mmol) and the 4-fluorobenzoic acid ethyl ester of 10.2g (60.95mmol) are placed round-bottomed flask, be dissolved in the 50mL anhydrous tetrahydro furan.Mixture is cooled to 0 ° of C, drips 70mL (70mmol) hexamethyl two silica-based Lithamide solution (tetrahydrofuran solution of 1M).After the interpolation, mixture is cooled to 5 ° of C stirring at room 2 hours, adds 100mL water then gradually.Medium uses 250mL ETHYLE ACETATE and the dilution of 100mL water then.Isolate organic phase, water uses the 100mL ethyl acetate extraction twice.Merge organic phase then, use dried over sodium sulfate, and filter.Add 15g silicon-dioxide to filtrating then, stir the mixture that obtains, under reduced pressure concentrate then.The powder that obtains uses the mixture wash-out of hexanaphthene and ETHYLE ACETATE (9/1) as the solid sediment of silica gel column chromatography.Obtain 7.5g (88%) product, be the form of yellow powder.
LC-MS:M+H=294 (keto-acid/enol form ratio: 43/57).
1H?NMR(DMSO)δ(ppm)：4.56(s,2H)；6.34(s,1H)；7.23-7.40(m,5H)；7.53(d,1H)；7.56(m,1H)；7.70(d,1H)；7.81-7.92(m,2H)；8.04-8.16(m,2H)；8.29(d,1H)；8.37(d,1H)；15.0(s,1H)。
5.2 2-(4-bromopyridine-2-yl)-1-(4-fluorophenyl) ethyl ketone oxime
2-(4-bromopyridine-2-yl)-1-(4-fluorophenyl) ethyl ketone of 7.5g (24.26mmol) is placed round-bottomed flask (containing the 100mL absolute ethyl alcohol).Add 20mL (247.78mmol) pyridine and 7.08g (101.88mmol) azanol mono-hydrochloric salts, medium is then stirring at room 3 hours.Ethanol goes out in vacuum-evaporation then, and the resistates that obtains is dissolved in 250mL water and 250mL ETHYLE ACETATE.Isolate organic phase, water uses the 150mL ethyl acetate extraction 5 times then.Merge organic phase then, use dried over sodium sulfate, under vacuum, concentrate.Obtain the 7.82g product.
LC-MS：M+H=309。
1H NMR (DMSO-d
6, δ, ppm): 4.26 (s, 2H); 7.19 (t, 2H); 7.50 (m, 2H); 7.75 (m, 2H); 8.33 (d, 1H); 11.50 (s, 1H) (oxime (E) generation).
5.3 5-bromo-2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine
2-(4-bromopyridine-2-yl)-1-(4-fluorophenyl) ethyl ketone oxime of 7.82g (25.50mmol) is placed round-bottomed flask, is dissolved in 1 of 400mL, the 2-ethylene dichloride.In the medium that is cooled to about 0 ° of C, drip O-(mesitylene alkylsulfonyl) hydroxylamine solutions (1 of 0.27M, the compound of 2-dichloroethane solution-obtain according to the scheme of describing in the step 1.3).After the interpolation, medium was stirring at room 1 hour 30 minutes.Medium uses 200mL water and 200mL sodium hydroxide solution (1N) dilution then.Stir two-phase medium, then through each phase of standing separation.Isolate organic phase, water uses the 200mL dichloromethane extraction 4 times then.Merge organic phase then, use dried over sodium sulfate, and filter.Then 15g silica gel is added in the filtrating, the mixture that obtains under reduced pressure concentrates then.The powder that obtains uses the mixture wash-out of hexanaphthene and methylene dichloride (1/1) as the solid sediment of silica gel column chromatography.Obtain 5.06g (68%) compound, be fluffy white powder.
LC-MS：M+H=291。
1H?NMR(DMSO-d
6,δ,ppm)：7.00-7.10(m,2H)；7.45(m,2H)；8.05(m,3H)；8.70(d,1H)。
5.4 3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] benzoic acid methyl ester
Under nitrogen gas stream; 5-bromo-2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine, the 3-methoxycarbonyl phenyl-boron dihydroxide of 0.300g (1.67mmol) and 9/1 mixture that 1.330g (4.08mmol) cesium carbonate places 5mL THF and water of the 0.400g (1.37mmol) that step 5.3 is obtained.[1,1 '-two (diphenylphosphine) ferrocene] dichloro that adds 0.11g (0.13mmol) closes palladium (II), and medium was 70 ° of C heating 4 hours.Then medium is cooled to room temperature, uses the dilution of 40mL methylene dichloride and 40mL water.Medium is gone up at drainage column (
70mL liquid phase/liquid-phase extraction post) then and is filtered; Reclaim organic phase; After adding 2g silicon-dioxide, under reduced pressure concentrate.Resistates uses the mixture wash-out of hexanaphthene and ETHYLE ACETATE (9/1) through the silica gel column chromatography purifying.Obtain 0.340g (71%) expectation product, be the form of white powder.
Fusing point (° C): 162-164.
LC-MS：M+H=347。
1H?NMR(DMSO)δ(ppm)：3.95(s,3H)；7.15(s,1H)；7.30-7.38(m,3H)；7.70(t,1H)；8.00-8.15(m,5H)；8.35(m,1H)；8.80(d,1H)。
Embodiment 6:3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide (compound 6 in the table)
This method is carried out according to the method for describing among the embodiment 3; Originate in 3-[2-(4-fluorophenyl) pyrazolo [1 of the 0.200g (0.58mmol) of step 7.4 acquisition; 5-a] pyridine-5-yl] benzoic acid methyl ester, 1.00mL (2.00mmol) methylamine solution (tetrahydrofuran solution of 2M) and 1.00mL (2.00mmol) trimethylaluminium solution (toluene solution of 2M), in 8mL toluene.Behind the silica gel column chromatography, use the mixture wash-out of hexanaphthene and ETHYLE ACETATE (1/1), obtain 0.235g (67.7%) expectation product, be the form of white powder.
Fusing point (° C): 214-216.
LC-MS：M+H=346。
1H?NMR(DMSO)δ(ppm)：2.85(d,3H)；7.15(s,1H)；7.26-7.46(m,3H)；7.62(m,1H)；7.90(m,1H)；8.00(m,1H)；8.05-8.21(m,3H)；8.29(m,1H)；8.60(m,1H)；8.82(d,1H)。
Embodiment 7:3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-2, N-dimethyl benzamide (compound 10 in the table)
7.1 2-(4-fluorophenyl)-5-(4,4,5,5-tetramethyl--[1,3,2] dioxa boron heterocycle pentane-2-yl) pyrazolo [1,5-a] pyridine (compound VI-1)
5-bromo-2-(4-fluorophenyl) pyrazolo [1 of the 1.00g (3.43mmol) that step 7.3 is obtained; 5-a] [1,1 '-two (diphenylphosphine) ferrocene] dichloro of two (tetramethyl ethylene ketone) two boron, 1.00g (10.19mmol) potassium acetate and 0.280g (0.34mmol) of pyridine and 1.05g (4.13mmol) closes palladium (II) and in 14mL two
alkane, mixes.
The medium that obtains uses 100mL methylene dichloride and 100mL water to dilute through 140 ° of C microwave irradiations 20 minutes then.Two-phase medium then drainage column (
70mL liquid phase/liquid-phase extraction post) filter.Reclaim organic phase, behind the interpolation 4g silicon-dioxide, under reduced pressure concentrate.The resistates silica gel column chromatography that obtains, the mixture wash-out of use hexanaphthene and ETHYLE ACETATE (9/1).Obtain 0.992g (85.4%) expectation product, be the pink colour form of powder.
LC-MS:M+H=338 (is decomposed into boric acid, M+H=257) on post
1H?NMR(DMSO)δ(ppm)：1.35(s,12H)；7.00(m,1H)；7.19(s,1H)；7.34(t,2H)；8.05(m,3H)；8.69(d,1H)。
7.2 3-bromo-2, the N-dimethyl benzamide
The 3-bromo-2-tolyl acid of 0.500g (2.33mmol) is placed round-bottomed flask (containing the N-hydroxybenzotriazole monohydrate of 1.51mL (10.83mmol) triethylamine, 0.408g (3.02mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide mono-hydrochloric salts and 5mL methylene dichloride of 0.579g (3.02mmol)).Medium then adds 1.51mL (3.02mmol) methylamine solution (tetrahydrofuran solution of 2M) stirring at room 1 hour.Medium then adds another part 0.5mL (1mmol) methylamine solution, the mixture stirred overnight in stirred overnight at room temperature.Medium under reduced pressure concentrates then, adds 5mL methylene dichloride and 0.390mL (2.99mmol) chloroformic acid isobutyl.Again with the medium stirred overnight, then through using the dilution of 7mL methylene dichloride and 7mL water.Medium and then drainage column (
70mL liquid phase/liquid-phase extraction post) are gone up and are filtered.Reclaim organic phase, under reduced pressure concentrate.Obtain 0.298g (56.2%) expectation product, be the form of white powder.
LC-MS：M+H=228。
1H?NMR(DMSO)δ(ppm)：2.31(s,3H)；2.80(d,3H)；7.05-7.35(m,2H)；7.68(m,1H)；8.32(bs,1H)。
7.3 3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-4, the N-dimethyl benzamide
2-(4-fluorophenyl)-5-(4 of the 0.150g (0.44mmol) that step 7.1 is obtained; 4,5,5-tetramethyl--[1; 3; 2] dioxa boron heterocycle pentane-2-yl) the 3-bromo-2-N-dimethyl benzamide of the 0.144g (0.63mmol) of pyrazolo [1,5-a] pyridine and step 10.2 acquisition and [1,1 '-two (diphenylphosphine) ferrocene] dichloro of 0.434g (1.33mmol) cesium carbonate and 0.036g (0.044mmol) close palladium (II) and in 9/1 mixture of 5mL THF and water, mix.Medium is 60 ° of C stirred overnight.Medium uses 50mL methylene dichloride and the dilution of 50mL water then.Two go up filtration at drainage column (
70mL liquid phase/liquid-phase extraction post) mutually then.Reclaim organic phase, behind the interpolation 1.5g silicon-dioxide, under reduced pressure concentrate.The resistates silica gel column chromatography that obtains, the mixture wash-out of use hexanaphthene and ETHYLE ACETATE (1/1).Obtain 0.103g (65%) expectation product, be the form of white powder.
Fusing point (° C): 240-242.
LC-MS：M+H=360。
1H?NMR(DMSO)δ(ppm)：2.37(s,3H)；2.80(d,3H)；6.86(d,1H)；7.10(s,1H)；7.33-7.44(m,5H)；7.63(s,1H)；8.10(m,2H)；8.28(s,1H)；8.76(d,1H)。
Embodiment 8:N-cyclopropyl-3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] BM (compound 15 in the table)
0.0382g (0.67mmol) cyclopropylamine is used the dilution of 10mL anhydrous tetrahydro furan.Add the DABAL (trimethylaluminium and 1, the diadduct of 4-diazabicyclo [2.2.2] octane) of 0.0859g (0.33mmol) then gradually, medium stirred 1 hour then.Add 3-[2-(4-fluorophenyl) pyrazolo [1, the 5-a] pyridine-5-yl] benzoic acid methyl ester of the 0.145g (0.42mmol) that obtains according to scheme 5.4 then, reaction medium then in the microwave still 130 ° of C shone twice 30 minutes.Medium utilizes 5mL water and 5mL aqueous hydrochloric acid (1N) hydrolysis at about 5 ° of C then.After the hydrolysis; Medium uses 50mL water and the dilution of 50mL methylene dichloride, filters through drainage column (
70mL liquid phase/liquid-phase extraction post) then.Reclaim organic phase, behind the interpolation 1.5g silicon-dioxide, under reduced pressure concentrate.The resistates silica gel column chromatography that obtains, the mixture wash-out of use hexanaphthene and ETHYLE ACETATE (6/4).Obtain 0.112g (72.3%) expectation product, be the form of white powder.
Fusing point (° C): 179-181.
LC-MS：M+H=372。
1H?NMR(DMSO)δ(ppm)：0.60-0.80(m,4H)；3.92(m,1H)；7.15(s,1H)；7.30-7.39(m,3H)；7.61(t,1H)；7.88(d,1H)；7.98(d,1H)；8.10(m,3H)；8.22(s,1H)；8.57(m,1H)；8.81(d,1H)。
Embodiment 9:{3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] phenyl }-(3-hydroxyl pyrrolidine-1-yl) ketone (compound 22 in the table)
To place round-bottomed flask (containing 0.170mL (1.20mmol) triethylamine and 20mL methylene dichloride) like 3-[2-(4-fluorophenyl) pyrazolo [1, the 5-a] pyridine-5-yl] phenylformic acid of the 0.100g (0.30mmol) of preparation among the embodiment 8.Add 0.051 μ L (0.39mmol) chloroformic acid isobutyl then, medium was stirring at room 2 hours.The 3-hydroxyl pyrrolidine of 0.0341g (0.39mmol) is added in the medium, again stirring at room 2 hours.Medium uses 50mL water and the dilution of 50mL methylene dichloride then.Two-phase medium filters through drainage column (
70mL liquid phase/liquid-phase extraction post) then.Reclaim organic phase, behind the interpolation 1g silicon-dioxide, under reduced pressure concentrate.The resistates silica gel column chromatography that obtains, the mixture wash-out of use hexanaphthene and ETHYLE ACETATE (6/4).Obtain 0.063g (50%) expectation product, be the form of light yellow wax.
Fusing point (° C): 173-175.
LC-MS：M+H=402。
1H?NMR(DMSO)δ(ppm)：1.65-2.05(m,2H)；3.40-3.70(m,4H)；4.32(d,1h)；5.00(d,1H)；7.11(s,1H)；7.32(m,3H)；7.60(m,2H)；7.93(d,2H)；8.08(m,3H)；8.77(d,1H)。
Embodiment 10:N-methyl-3-(2-p-methylphenyl pyrazolo [1,5-a] pyridine-5-yl) BM (compound 328 in the table)
10.1 2-(4-bromopyridine-2-yl)-1-p-methylphenyl ethyl ketone
Under nitrogen gas stream, the 4-bromo-2-picoline of 1g (5.81mmol) and the 4-tolyl acid methyl ester of 1.75g (11.60mmol) are placed round-bottomed flask, be dissolved in the 30mL anhydrous tetrahydro furan.Solution is cooled to 5 ° of C, drips 14mL (14mmol) hexamethyl two silica-based Lithamide solution (tetrahydrofuran solution of 1M).After the interpolation, mixture is cooled to 5 ° of C then stirring at room 2 hours 30 minutes, then adds 20mL water gradually.Medium uses 200mL ETHYLE ACETATE and the dilution of 200mL water then.Isolate organic phase, use dried over sodium sulfate, and filter.Then 5g silicon-dioxide is added in the filtrating, under reduced pressure concentrates then.The powder that obtains uses the mixture wash-out of hexanaphthene and ETHYLE ACETATE (95/5) as the solid sediment of silica gel column chromatography, obtains 1.03g (61%) product, is the form of yellow powder.
LC-MS：M+H=290。
10.2 4-bromo-2-(3-p-methylphenyl-2H-aziridine (azirin)-2-yl) pyridine
2-(4-bromopyridine-2-yl)-1-p-methylphenyl ethyl ketone of the 1.03g that step 13.1 is obtained places round-bottomed flask (containing 0.99g (14.2mmol) azanol mono-hydrochloric salts, 3mL (37mmol) pyridine and 100mL ethanol).The reaction medium stirred overnight under reduced pressure concentrates then.The resistates that obtains is dissolved in 200mL ETHYLE ACETATE and 200mL water then.Reclaim organic phase, use dried over sodium sulfate, under reduced pressure concentrate then.Reclaim the 1.10g compound, be dissolved in the round-bottomed flask that contains 0.660mL (4.74mmol) triethylamine and 30mL methylene dichloride.Reaction medium is cooled to about 5 ° of C then, drips 0.200mL (1.42mmol) trifluoroacetic anhydride.Medium stirring at room 3 hours, then uses 100mL water to be hydrolyzed then.Medium stirred 10 minutes then, then filtered through drainage column (
70mL liquid phase/liquid-phase extraction post).Then 1.2g silicon-dioxide is added in the filtrating, then under reduced pressure concentrates.The powder that obtains uses the mixture wash-out of hexanaphthene and ETHYLE ACETATE (95/5) as the solid sediment of silica gel column chromatography.Obtain 0.746g (77%) expectation product, be the form of white powder.
1H?NMR(DMSO)δ(ppm)：2.42(d,3H)；3.45(s,1H)；7.42-7.58(m,4H)；7.78(m,2H)；8.30(d,1H)。
10.3 5-bromo-2-p-methylphenyl-pyrazolo [1,5-a] pyridine
In the presence of 6.6mg (0.052mmol) iron(ic)chloride (II), 4-bromo-2-(3-p-methylphenyl-2H-aziridine-2-yl) pyridine of the 0.746g that step 13.2 is obtained is dissolved in 1 of 30mL, the 2-glycol dimethyl ether.Medium refluxed 6 hours then.And then adding 10mg (0.078mmol) iron(ic)chloride (II), the mixture restir refluxed 3 hours.Medium uses 50mL ETHYLE ACETATE and the dilution of 50mL water then.Reclaim organic phase, use dried over sodium sulfate, and filter.Then 2g silicon-dioxide is added into filtrating, then under reduced pressure concentrates.The powder that obtains uses the mixture wash-out of hexanaphthene and ETHYLE ACETATE (85/15) as the solid sediment of silica gel column chromatography.Obtain 0.534g (71%) expectation product, be the form of yellow powder.
LC-MS：M+H=287。
1H?NMR(DMSO)δ(ppm)：2.48(m,3H)；7.00(m,2H)；7.32(m,2H)；7.88(m,2H)；8.00(m,1H)；8.68(d,1H)。
10.4 N-methyl-3-(4,4,5,5-tetramethyl--[1,3,2] dioxa boron heterocycle pentane-2-yl) BM
With [1 of 3-bromo-N-methyl-benzamide, 3.56g (14.01mmol) two (tetramethyl ethylene ketone) two boron, 3.43g (35.04mmol) potassium acetate and the 0.953g (1.17mmol) of 2.50g (11.68mmol); 1 '-two (diphenylphosphine) ferrocene] dichloro closes palladium (II) and mixes with 20mL two
alkane, then 130 ° of C microwave irradiations 45 minutes.Medium uses 150mL ETHYLE ACETATE and the dilution of 100mL water then.Reclaim organic phase, water uses the 100mL ethyl acetate extraction twice.Merge organic phase then, use dried over sodium sulfate, behind the interpolation 10g silicon-dioxide, under reduced pressure concentrate then.The resistates silica gel column chromatography that obtains, the mixture wash-out of use hexanaphthene and ETHYLE ACETATE (8/2).Obtain 1.39g expectation product, be pink colour form of powder (having tetramethyl ethylene ketone).
1H?NMR(DMSO)δ(ppm)：1.30(s,12H)；2.78(d,3H)；7.48(t,1H)；7.80(m,1H)；7.95(m,1H)；8.12(m,1H)；8.50(m,1H)。
10.5 N-methyl-3-(2-p-methylphenyl pyrazolo [1,5-a] pyridine-5-yl) BM
The 5-bromo-2-p-methylphenyl pyrazolo [1 of the 0.150g (0.52mmol) that step 13.3 is obtained; 5-a] N-methyl-3-(4,4,5 of the 0.136g (0.52mmol) that obtains of pyridine, step 13.4; 5-tetramethyl--[1; 3,2] dioxa boron heterocycle pentane-2-yl) [1,1 '-two (diphenylphosphine) ferrocene] dichloro of BM, 0.510g (1.57mmol) cesium carbonate and 0.043g (0.05mmol) closes 9/1 mixture that palladium (II) places 5mL THF and water.Medium stirred 4 hours at 65 ° of C.Medium uses 50mL methylene dichloride and the dilution of 50mL water then.Two-phase medium filters through drainage column (
70mL liquid phase-liquid-phase extraction post) then.Reclaim organic phase, behind the interpolation 1.5g silicon-dioxide, under reduced pressure concentrate.The resistates silica gel column chromatography that obtains, the mixture wash-out of use hexanaphthene and ETHYLE ACETATE (1/1).Obtain 0.138g (77.7%) expectation product, be the form of cream-coloured powder.
Fusing point (° C): 204-206.
LC-MS：M+H=342。
1H?NMR(DMSO)δ(ppm)：2.38(s,3H)；2.85(d,3H)；7.10(s,1H)；7.31(m,3H)；7.62(t,1H)；7.90(m,3H)；7.98(d,1H)；8.08(s,1H)；8.29(s,1H)；8.61(d,1H)；8.81(d,1H)。
Embodiment 11:3-[3-chloro-2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide (compound 34 in the table)
3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide of the 0.100g (0.29mmol) that will obtain according to scheme 6 places round-bottomed flask (containing the 3mL methylene dichloride).Add the N-chlorosuccinimide of 0.060g (0.45mmol), medium is then in stirred overnight at room temperature.Reaction medium uses 50mL methylene dichloride and the dilution of 50mL water then.Two-phase medium filters through drainage column (
70mL liquid phase/liquid-phase extraction post) then.Reclaim organic phase, behind the interpolation 1.2g silicon-dioxide, under reduced pressure concentrate.The resistates silica gel column chromatography that obtains, the mixture wash-out of use hexanaphthene and ETHYLE ACETATE (6/4).Obtain 0.0592g (53.8%) expectation product, be the form of white powder.
Fusing point (° C): 221-223.
LC-MS：M+H=380。
1H?NMR(DMSO)δ(ppm)：2.88(d,3H)；7.42(m,2H)；7.47(dd,1H)；7.64(t,1H)；7.93(m,1H)；8.01(m,1H)；8.05(m,1H)；8.10(m,2H)；8.31(m,1H)；8.63(m,1H)；8.88(d,1H)。
The chemical structure (table 1) of following table exemplary illustration general formula (I) and according to the physico-chemical property (table 2) of many embodiment compounds of the present invention.
In these tables:
The fusing point of-hurdle " m.p. " expression product, unit is degree centigrade (a ° C);
-Me and Et represent methyl and ethyl respectively;
-* representes linker atom.
Table 1
Table 2
Compound of the present invention carries out the pharmacology test and is used for confirming their regulating effects to NOT.
To the active assessment of N2A cells in vitro
The activity of The compounds of this invention is estimated in clone (N2A); This clone endogenous expression mouse Nurr1 acceptor also combines response element (NOT binding response element with NOT; NBRE) stable transfection, this NBRE and the coupling of luciferase reporter gene.The step that this test is described according to hereinafter is carried out.
Clone Neuro-2A is from normal business source (ATCC).The spontaneous knurl that clone's Neuro-2A origin comes from albefaction mouse diseased plant people such as () R.J Klebe obtains.Use this clone of 8NBRE-luciferase stable transfection Neuro-2A then.This N2A-8NBRE cell is cultured to merging point in 75cm2 contains the culturing bottle of the DMEM that is supplemented with 10% foetal calf serum, 4.5g/L glucose and 0.4mg/ml Geneticin.After cultivating a week, cell uses 0.25% trypsinase to recover 30 seconds, and then is suspended in and does not contain phenol red DMEM (containing 4.5g/L glucose and 10%Hyclone degreasing serum), and places white clear bottom 96 orifice plates.Cell precipitates 24 hours with the ratio in every hole 60 000 in 75 μ L, add product then.Product is used with 25 μ L, and cultivates 24 hours again.On the same day of measuring, in every hole, add isopyknic (100 μ L) Steadylite, then each hole is left standstill 30 minutes to obtain the signal that dissolves and produce maximum fully of this cell.After then this plate being used the adhesive film sealing, measure at the micro plate luminescent counter.Product is with 10
-2The prepare of M storing solution is diluted in 100%DMSO then.The product of each concentration with cell cultures before, be diluted in substratum in advance, thereby finally contain 0.625% DMSO.
The EC of best compound
50Value is between 0.1nM to 10 μ M.
For example, the EC that shows respectively of compound 2,4,10,14,16 and 26
50Value is 45; 2; 6.6; 125; 326 and 1.3nM.
Therefore, can find out that compound of the present invention has regulating effect to NOT.
Therefore, compound of the present invention can be used for preparing the medicine that is used to treat or prevent to relate to the disease of NOT acceptor.
Therefore, according to others, the medicine that themes as of the present invention, it contains the additive salt that formula (I) compound or itself and pharmaceutically acceptable acid form.
These medicines can be used for therepic use, especially in treatment and prevention neurodegenerative disease, for example Parkinson's disease, alzheimer's disease, Tau pathology (for example, stein-leventhal syndrome, frontotemporal dementia, corticobasal degeneration, Pick's disease); Cerebral trauma (cerebral trauma), for example ischemic and craniocerebral trauma (cranial trauma) and epilepsy; Psychosis, for example schizophrenia, depression, substance depilatory property (substance dependency) and attention deficit move obstacle more; The inflammatory diseases of cns; For example multiple sclerosis, encephalitis, myelitis and encephalomyelitis; With other inflammatory diseasess, for example vascular lesion (vascularpathologies), atherosclerosis, arthritis (joint inflammations), joint disease, rheumatoid arthritis; Osteo-arthritis, Crohn disease, ulcerative colitis; Abnormalism inflammatory diseases, for example asthma, autoimmune disorder, for example type i diabetes, lupus, scleroderma, Guillain-Barre&1& syndrome, Addison's disease and other immune-mediated diseases; Osteoporosis; Cancer.
These compounds also can be used as and the graft of stem cell and/or the treatment of transplanting combination.
According to other aspects of the invention, the present invention relates to pharmaceutical composition and comprise compound of the present invention as activeconstituents.These pharmaceutical compositions contain the compound at least a of the present invention of significant quantity or the pharmacy acceptable salt of said compound, and at least a pharmaceutically acceptable vehicle.
From the known conventional excipients of those of ordinary skills, select said vehicle according to pharmaceutical dosage form and required route of administration.
In being used for oral, hypogloeeis, subcutaneous, intramuscular, intravenously, part (topical), surface (local), tracheae, nose in, through the pharmaceutical composition of the present invention of skin or rectal administration, the activeconstituents of above-mentioned formula (I) or its salt can with the unit form of medication (as with the mixture of the medical vehicle of standard) be administered to humans and animals and be used for preventing or treating above-mentioned disease or illness.
Suitable administration unit form comprises in oral forms such as tablet, soft gel capsule or hard gel capsule, powder, particle or oral liquid or suspension-s, hypogloeeis, the oral cavity, in the tracheae, in the intraocular, nose or the inhalation form; Local, through skin, subcutaneous, intramuscular or intravenous administration form, rectal administration form and implant.For topical application, compound of the present invention can use in emulsion, gel, ointment or lotion.
For example, the tablet of the unit form of medication of The compounds of this invention can comprise following ingredients:
Can exist and have higher or be suitable particular case than low dosage; This type of dosage does not exceed scope of the present invention.According to conventional actually operating, confirm with response according to mode of administration and said patient's body weight by the doctor for each patient's appropriate dosage.
According to other aspects, the invention still further relates to a kind of method of treating pathology as implied above, it comprises to the compound of the present invention of patient's effective dosage or its pharmacy acceptable salt.
Claims (17)
1. formula (I) compound:
Wherein:
R representes hydrogen or halogen atom or (C1-C6) alkyl;
X representes one or more following substituting groups that are selected from: hydrogen or halogen atom, (C1-C6) alkyl, halo (C1-C6) alkyl, (C1-C6) alkoxyl group, halo (C1-C6) alkoxyl group, cyanic acid, hydroxyl or hydroxyl (C1-C6) alkyl;
Y representes hydrogen or halogen atom or (C1-C6) alkyl;
R1 representes NR2R3 or OR4;
R2 and R3 represent Wasserstoffatoms or (C1-C6) alkyl, hydroxyl (C1-C6) alkyl or oxo (C1-C6) alkyl independently of one another, perhaps R2 and R3 and the nitrogen-atoms that carries them form optional by (C1-C6) alkyl, hydroxyl or the substituted heterocycle of oxo,
R4 representes (C1-C6) alkyl, hydroxyl (C1-C6) alkyl or oxo (C1-C6) alkyl,
Form with alkali form or acid salt.
2. the formula of claim 1 (I) compound is characterized in that:
R representes hydrogen or chlorine atom,
X representes one or more following substituting groups that are selected from: halogen atom, (C1-C6) alkyl, halo (C1-C6) alkyl, (C1-C6) alkoxyl group, halo (C1-C6) alkoxyl group or cyanic acid,
Y representes Wasserstoffatoms, halogen atom or (C1-C6) alkyl;
R1 representes OR4,
R4 representes methyl,
Form with alkali form or acid salt.
3. the formula of claim 1 (I) compound is characterized in that:
R representes hydrogen or chlorine atom,
X representes one or more following substituting groups that are selected from: chlorine or fluorine atom, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy or cyanic acid,
Y representes hydrogen, chlorine or fluorine atom or methyl,
R1 representes OR4,
R4 representes methyl,
Form with alkali form or acid salt.
4. the formula of claim 1 (I) compound is characterized in that:
R representes hydrogen or chlorine atom,
X representes one or more following substituting groups that are selected from: halogen atom, (C1-C6) alkyl, halo (C1-C6) alkyl, (C1-C6) alkoxyl group, halo (C1-C6) alkoxyl group or cyanic acid,
Y representes Wasserstoffatoms, halogen atom or (C1-C6) alkyl;
R1 representes NR2R3,
R2 and R3 represent Wasserstoffatoms or methyl, ethyl, sec.-propyl or cyclopropyl independently of one another, perhaps R2 and R3 and the nitrogen-atoms that carries them form optional by substituted morpholinyl of hydroxyl or pyrrolidyl,
Form with alkali form or acid salt.
5. the formula of claim 1 (I) compound is characterized in that:
R representes hydrogen or chlorine atom,
X representes one or more following substituting groups that are selected from: chlorine or fluorine atom, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy or cyanic acid,
Y representes hydrogen or chlorine atom or methyl,
R1 representes NR2R3,
R2 and R3 represent Wasserstoffatoms or methyl, ethyl, sec.-propyl or cyclopropyl independently of one another, perhaps R2 and R3 and the nitrogen-atoms that carries them form optional by substituted morpholinyl of hydroxyl or pyrrolidyl,
Form with alkali form or acid salt.
6. compound:
3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl] benzoic acid methyl ester
3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl] BM
3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl]-N, the N-dimethyl benzamide
3-[2-(4-chloro-phenyl-) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] benzoic acid methyl ester
3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-isopropyl benzene methane amide
3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N, the N-dimethyl benzamide
{ 3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] phenyl } morpholine-4-base-ketone
3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-2, the N-dimethyl benzamide
2-chloro-5-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
4-chloro-3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-4, the N-dimethyl benzamide
2-fluoro-4-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
N-cyclopropyl-3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] BM
{ 3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] phenyl } tetramethyleneimine-1-base ketone
3-[2-(2, the 6-difluorophenyl) pyrazolos [1,5-a] pyridine-5-base-methyl benzamide
3-[2-(2-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
N-methyl-3-[2-(4-trifluoromethyl) pyrazolo [1,5-a] pyridine-5-yl] BM
4-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
2-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
{ 3-[2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl] phenyl }-(3-hydroxyl pyrrolidine-1-yl) ketone
3-[2-(2,4 difluorobenzene base) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
N-methyl-3-[2-(4-Trifluoromethoxyphen-l) pyrazolo [1,5-a] pyridine-5-yl] BM
3-[2-(3, the 4-difluorophenyl) pyrazolos [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(3, the 5-difluorophenyl) pyrazolos [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(3-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
N-methyl-3-(2-p-methylphenyl pyrazolo [1,5-a] pyridine-5-yl) BM
3-[2-(4-p-methoxy-phenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(3, the 4-3,5-dimethylphenyl) pyrazolos [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(4-cyano-phenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide
3-[2-(2, the 3-difluorophenyl) pyrazolos [1,5-a] pyridine-5-yl]-N-methyl-benzamide
N-methyl-3-(2-o-tolyl pyrazolo [1,5-a] pyridine-5-yl) BM
3-[3-chloro-2-(4-fluorophenyl) pyrazolo [1,5-a] pyridine-5-yl]-N-methyl-benzamide.
7. medicine is characterized in that the additive salt that formula (I) compound that it comprises among the claim 1-6 each or this compound and pharmaceutically acceptable acid form.
8. pharmaceutical composition is characterized in that it comprises among the claim 1-6 each formula (I) compound or the pharmacy acceptable salt of this compound, and at least a pharmaceutically acceptable vehicle.
9. the purposes that each formula (I) compound is used for treating and preventing the medicine of neurodegenerative disease among the claim 1-6 in preparation.
10. each formula (I) compound is used for treating the purposes with the medicine of prevention of brain wound and epilepsy in preparation among the claim 1-6.
11. the purposes that each formula (I) compound is used for treating and preventing psychotic medicine among the claim 1-6 in preparation.
12. the purposes that each formula (I) compound is used for treating and preventing the medicine of inflammatory diseases among the claim 1-6 in preparation.
13. each formula (I) compound is used for treating the purposes with the medicine of preventing osteoporosis disease and cancer in preparation among the claim 1-6.
14. each formula (I) compound is used for treating and prevent the purposes of the medicine of parkinson's disease, Alzheimer, Tau pathology and multiple sclerosis among the claim 1-6 in preparation.
15. each formula (I) compound is used for treating the purposes of moving the medicine of obstacle with prevention of schizophrenia, depression, substance depilatory property and attention deficit in preparation more among the claim 1-6.
16. the midbody compound of formula (VI-1)
17. the purposes of the compound of claim 16 in general formula (I) product of synthetic claim 1.
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| FR0958651 | 2009-12-04 | ||
| FR0958651A FR2953520B1 (en) | 2009-12-04 | 2009-12-04 | DIPHENYL-PYRAZOLOPYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| PCT/FR2010/052605 WO2011067544A1 (en) | 2009-12-04 | 2010-12-03 | Diphenyl-pyrazolopyrdine derivatives, preparation thereof, and use thereof as nuclear receptor not modulators |
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| US (1) | US8680096B2 (en) |
| EP (1) | EP2507238B1 (en) |
| JP (1) | JP5738310B2 (en) |
| KR (1) | KR101696959B1 (en) |
| CN (1) | CN102762559B (en) |
| AR (1) | AR079250A1 (en) |
| AU (1) | AU2010326429B2 (en) |
| BR (1) | BR112012013511A2 (en) |
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| CL (1) | CL2012001461A1 (en) |
| CO (1) | CO6551713A2 (en) |
| EA (1) | EA020652B1 (en) |
| FR (1) | FR2953520B1 (en) |
| HK (1) | HK1169984A1 (en) |
| IL (1) | IL220060A (en) |
| JO (1) | JO3098B1 (en) |
| MA (1) | MA33893B1 (en) |
| MX (1) | MX2012006421A (en) |
| MY (1) | MY157676A (en) |
| NZ (1) | NZ600368A (en) |
| SG (1) | SG181138A1 (en) |
| TW (1) | TWI481606B (en) |
| UY (1) | UY33079A (en) |
| WO (1) | WO2011067544A1 (en) |
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|---|---|---|---|---|
| CN110049975A (en) * | 2016-12-08 | 2019-07-23 | 拜耳作物科学股份公司 | 5- (1- phenyl -1H- pyrazoles -4- base) nicotinamide derivates and similar compound are prepared without the method for isolated or purified phenylhydrazine intermediate |
| CN111138325A (en) * | 2019-12-20 | 2020-05-12 | 台州学院 | Preparation method of (Z) - β -sulfonyl enamine compound |
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| FR2950344B1 (en) * | 2009-09-18 | 2011-11-25 | Sanofi Aventis | 5-PHENYL-PYRAZOLOPYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR USE IN THERAPEUTICS. |
| FR2950345B1 (en) * | 2009-09-18 | 2011-09-23 | Sanofi Aventis | ACETYLENE DERIVATIVES OF 5-PHENYL-PYRAZOLOPYRIDINE, THEIR PREPARATION AND THEIR THERAPEUTIC USE |
| WO2018098491A1 (en) | 2016-11-28 | 2018-05-31 | Praxis Precision Medicines, Inc. | Compounds and their methods of use |
| CN116763791A (en) | 2016-11-28 | 2023-09-19 | 普拉克西斯精密药物股份有限公司 | Compounds and methods of use thereof |
| US20210188839A1 (en) * | 2016-11-28 | 2021-06-24 | Praxis Precision Medicines, Inc. | Compounds and their methods of use |
| WO2018148745A1 (en) | 2017-02-13 | 2018-08-16 | Praxis Precision Medicines , Inc. | Compounds and their methods of use |
| WO2018187480A1 (en) | 2017-04-04 | 2018-10-11 | Praxis Precision Medicines, Inc. | Compounds and their methods of use |
| US11278535B2 (en) | 2017-08-15 | 2022-03-22 | Praxis Precision Medicines, Inc. | Compounds and their methods of use |
| CN117756800A (en) | 2018-05-30 | 2024-03-26 | 普拉克西斯精密药物股份有限公司 | Ion channel modulators |
| US11773099B2 (en) | 2019-05-28 | 2023-10-03 | Praxis Precision Medicines, Inc. | Compounds and their methods of use |
| US11279700B2 (en) | 2019-05-31 | 2022-03-22 | Praxis Precision Medicines, Inc. | Ion channel modulators |
| US11505554B2 (en) | 2019-05-31 | 2022-11-22 | Praxis Precision Medicines, Inc. | Substituted pyridines as ion channel modulators |
| US11767325B2 (en) | 2019-11-26 | 2023-09-26 | Praxis Precision Medicines, Inc. | Substituted [1,2,4]triazolo[4,3-a]pyrazines as ion channel modulators |
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Also Published As
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| JP2013512884A (en) | 2013-04-18 |
| MY157676A (en) | 2016-07-15 |
| UY33079A (en) | 2011-06-01 |
| CO6551713A2 (en) | 2012-10-31 |
| IL220060A (en) | 2015-05-31 |
| EP2507238A1 (en) | 2012-10-10 |
| JP5738310B2 (en) | 2015-06-24 |
| BR112012013511A2 (en) | 2016-06-07 |
| AU2010326429B2 (en) | 2016-07-14 |
| US8680096B2 (en) | 2014-03-25 |
| AR079250A1 (en) | 2012-01-04 |
| KR20120103672A (en) | 2012-09-19 |
| JO3098B1 (en) | 2017-03-15 |
| HK1169984A1 (en) | 2013-02-15 |
| CN102762559B (en) | 2014-11-05 |
| FR2953520B1 (en) | 2011-11-25 |
| EA201290520A1 (en) | 2013-01-30 |
| FR2953520A1 (en) | 2011-06-10 |
| WO2011067544A1 (en) | 2011-06-09 |
| CA2782704C (en) | 2018-01-02 |
| US20120245164A1 (en) | 2012-09-27 |
| KR101696959B1 (en) | 2017-01-16 |
| TW201129564A (en) | 2011-09-01 |
| CL2012001461A1 (en) | 2012-10-12 |
| MA33893B1 (en) | 2013-01-02 |
| TWI481606B (en) | 2015-04-21 |
| EA020652B1 (en) | 2014-12-30 |
| NZ600368A (en) | 2013-12-20 |
| EP2507238B1 (en) | 2013-07-31 |
| CA2782704A1 (en) | 2011-06-09 |
| MX2012006421A (en) | 2012-10-09 |
| AU2010326429A1 (en) | 2012-06-21 |
| SG181138A1 (en) | 2012-07-30 |
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